title: Synthesis of marine α-methoxylated fatty acid analogs that effectively inhibit the topoisomerase IB from Leishmania donovani with a mechanism different from that of camptothecin.
abstract: Sponges biosynthesize α-methoxylated fatty acids with unusual biophysical and biological properties and in some cases they display enhanced anticancer activities. However, the antiprotozoal properties of the α-methoxylated fatty acids have been less studied. In this work, we describe the total synthesis of (5Z,9Z)-(±)-2-methoxy-5, 9-eicosadienoic acid (1) and its acetylenic analog (±)-2-methoxy-5,9-eicosadiynoic acid (2), and report that they inhibit (EC₅₀ values between 31 and 22 µM) the Leishmania donovani DNA topoisomerase IB enzyme (LdTopIB). The inhibition of LdTopIB (EC₅₀ = 53 µM) by the acid (±)-2-methoxy-6-icosynoic acid (12) was studied as well. The potency of LdTopIB inhibition followed the trend 2 > 1 > 12, indicating that the effectiveness of inhibition depends on the degree of unsaturation. All of the studied α-methoxylated fatty acids failed to inhibit the human topoisomerase IB enzyme (hTopIB) at 100 µM. However, the α-methoxylated fatty acids were capable of inhibiting an active but truncated LdTopIB with which camptothecin (CPT) cannot interact suggesting that the methoxylated fatty acids inhibit LdTopIB with a mechanism different from that of CPT. The diunsaturated fatty acids displayed low cytotoxicity towards Leishmania infantum promastigotes (EC₅₀ values between 260 and 240 µM), but 12 displayed a better cytotoxicity towards Leishmania donovani promastigotes (EC₅₀ = 100 µM) and a better therapeutic index.
authors.affiliation: Department of Chemistry, University of Puerto Rico, PO Box 23346, San Juan 00931-3346, Puerto Rico. nestor.carballeira1@upr.edu.
authors.forename: Néstor M
authors.initials: NM
authors.lastname: Carballeira
authors.forename: Nashbly
authors.initials: N
authors.lastname: Montano
authors.forename: Raquel
authors.initials: R
authors.lastname: Alvarez-Velilla
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Prada
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Reguera
authors.forename: Rafael
authors.initials: R
authors.lastname: Balaña-Fouce
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects*; D059004:Topoisomerase I Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000981:Antiprotozoal Agents; D005231:Fatty Acids, Unsaturated; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin